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After a roller coaster ride from the patent office to the High Court and back to the Patent Office, the application for Patent for Sovaldi (Sofosbuvir) has now finally seen the sun. The Indian Patent Office has upheld the patent application of Gilead for Sofosbuvir. The Dy. Controller of Patents and Designs, Mr. Rajesh Dixit, in a 58 page order has found the application for patent to be novel, inventive and outside the prohibitory ambit of Section 3(d).

The Indian Patent office had earlier in January 2015 rejected the same application under Section 3(d) of the Indian Patents Act. Instead of appointing hearings on the pre-grant oppositions, the erstwhile Controller appointed a hearing under Section 15. The Controller did not consider the data on reduced toxicity and rejected Gilead’s patent application under Section 3(d). Gilead had filed a Writ Petition before the Delhi High Court against the Order of the Controller stating that the same was biased and was largely influenced by the opposition filed to the extent that typographical errors in the oppositions filed were incorporated as it is in the order. Gilead further claimed that the order was biased as no opportunity of being heard was given to the Petitioner with regard to the grounds raised in the oppositions. The order was set aside and the matter was remanded back for a fresh hearing by the Delhi high Court.

Dr. Rajesh Dixit heard the matter at length between 23rd to 29th February 2016 and vide an order dated 9th May 2016 reversed the previous order refusing the grant. The following are noteworthy findings in the decision of the Controller:-

(a)Novelty

1) The application discloses (2’R)-21-deoxy-2’-fluoro (down)-2’-C-methyl (up) nucleosides, as well as their corresponding monophosphate, diphosphate and triphosphate forms. The claimed compounds require methyl group at the 2’(up) position and a fluorine at the 2’(down) position of the sugar ring, a cytosine or uracil base attached to the sugar ring at 1 position nitrogen in the base ring.

2) The Controller noted that this substitution is unique and there is neither exemplification nor enabling disclosure in any of the cited prior art documents, including the closest prior art WO425, of the compounds claimed in the present application. The claimed compounds which have not be exemplified in any prior art cannot be deemed to be a part of the prior art.

3) Cherry picking of substituents from prior art is not allowed and the substituent in the Markush formulae provided in the prior arts have to be understood in the context of the invention contained in the examples, process for preparation and overall teaching of the document. Arbitrary selection of the substituents to arrive at hypothetical compounds is not possible without hindsight.

(b)Inventive Step

4) The Controller held that the compounds enabled by the prior art do not have 2’-fluoro (down)-2’-C-methyl (up) substitution pattern, which has been claimed in the present application. From the teachings of prior art, in particular WO425, it is difficult for POSA to arrive at a substitution pattern as presently claimed. There is no motivation or guidance towards the unique substitution pattern of the compounds of the present application in WO425 or any other prior art document.

5) A person skilled in the art would not be motivated to select a compound for further research from prior art unless the same is enabled or listed as a promising compound. Selecting a hypothetical compound requires some motive. The opponent has not provided any motivation for selecting said imaginary compound for the inventive step analysis.

6) POSA was further well aware of the unpredictability of fluorination on drug metabolism and unpredictability of fluorination using reagents such as DAST and substantial experimentation would have been required at the priority date to arrive at the claimed compounds which therefore, cannot be obvious.

(c)Section 3(d)

7) The Controller held that the compounds claimed are outside the prohibitory ambit of Section 3(d).

8) Nucleosides and other analogues are known in the art and in further research in the field there is bound to be similarity in core structure of any new nucleoside analogue invented. This cannot be understood to mean the structural similarity in field of chemistry. Further if such compounds are considered to be structurally similar and a derivative then the issue will be that what would be the known substance against which the enhanced therapeutic efficacy has to be shown.

9) The compounds argued to be known substances for the present case are hypothetical compounds which are not exemplified. The processes described in the prior art will not lead to the claimed compounds. In other words, the claimed compounds can be visualized in the prior art only by way of hindsight. An applicant cannot be required to make a compound which was not in existence as on the priority date for showing comparative activities.

10) Further, the claimed compounds are not polymorphs, isomers, salts etc. of a known compound and therefore are not derivatives of any known compounds. The process for the preparation of the claimed compounds shows that the claimed compounds are not derived from compounds having 2’methyl (up) or 2’-hydroxyl (down) substitutions.

11) In addition, the applicant has provided comparative activity and toxicity data vis-à-vis compounds having 2’methyl (up) substitution and 2’-hydroxyl (down) substitution i.e. 2’-C-methylcytidine and 2’-C-methyladenosine. The drug cover by the claims of the present application has shown excellent efficacy as against all the known medicines for HCV.

(d)Insufficiency

12) Though the Opponents argued that the claimed compounds are not sufficiently described in the complete specification this claim has not been supported by any reason. The specification provides examples, schemes of synthesis, experimental data, figures, comparative activity and toxicity data. Therefore, a person skilled in art will able to perform the invention in view of the description of the patent application.

In a recent decision, Justice Manmohan Singh of the Delhi High Court has restrained Biocon and Mylan to sell, manufacture, market and advertise their Trastuzumab as a bio similar to Roche’s Trastuzumab which is sold under the brand names of HERCEPTIN®, HERCLON™ and BICELTIS®.

Trastuzumab enjoys a global reputation for being an accepted biological treatment for HER 2 positive breast cancer worldwide. The facts of the case are as follows:

Roche Products is the importer and marketer of this innovator molecule in India. Biocon Limited co-developed and purported biosimilar version of Trastuzumab, along with Mylan Inc. and obtained an approval to market and sell the biosimilar version of Trastuzumab. Roche filed a suit for injunction against Biocon, Mylan Inc., and Mylan Pharmaceuticals Private Ltd. The Drug Controller General of India (DGCI) who granted the approval to Biocon and Mylan was also made a party to the suit.

Roche contended that the defendants’ drugs are, inter alia, being misrepresented as “Trastuzumab”, “biosimilar Trastuzumab” and a biosimilar version of HERCEPTIN® without following due process for obtaining appropriate approvals in accordance with the Guidelines on Similar Biologics. Roche also argued that Biocon has not conducted various tests required under the law for drug approval including Phase I and Phase II trials. The defendant has also not independently generated requisite data in order to demonstrate similarity between the drug and the plaintiffs’ Trastuzumab, both in terms of the stages and the sample size of the tests conducted by defendant No.2.

It was also averred that as per the procedure for the approval of new drugs in India, after New Drugs Advisory Committee (NDAC) has reviewed an application for a new drug and given its recommendation, it refers such application to a Technical Committee (the “TC”), for consideration along with its recommendation. After the TC has endorsed the recommendation made by NDAC, it refers the application to the Apex Committee, and only after both TC and the Apex Committee have endorsed the recommendation of the NDAC, should defendant No.1 consider granting its approval to such an application.

This is usually a time consuming process and the consideration by the NDAC, the TC and the Apex Committee , but however this was done in a short span of five days i.e. between 18th October to 23rd October, 2013. The undue haste with which the approval was granted suggests that all factors relevant to the approval of a biosimilar drug under the Guidelines on Similar Biologies and under other internationally recognised standards were not taken into consideration at the time of granting such an approval.

The defendants argued that the application for manufacture of its drug was in conformance with the statutory requirements as contained in the relevant rules read with schedule Y of the Drugs & Cosmetics Act. under the said Act and corresponding Rules, the term “Similar Biologics” has not been defined. However, the DCGI along with the Department of Bio -Technology had prepared “Guidelines on Similar Biologics: Regulatory Requirement for Marketing Authorization in India” in the year 2012. These guidelines are not statutory under the Drugs and Cosmetics Act and the Rules made thereunder. It was averred by the defendants that though the clinical trials of Phase I and Phase II have not been registered with the defendant No.1 but it did not skip Phase I trial as the main the objective of a Phase I trial is to establish comparative pharmacokinetics (pK) and this pK data was generated as the initial part of the Phase III trial. Defendant No.2 tried to give its justification for not doing the Phase II study as dose finding and POC studies are not required for follow-on products (biosimilars or generics).

Considering the overall facts and circumstances, Justice Manmohan Singh made the following prima-facie observations:-

– the approvals as per existing protocol of biosimilar drug are contrary to the Rules, Guidelines of Biosimilar 2012 as well as directions issued by the Supreme Court.

– the approvals which are in the hands of defendants are not in accordance with the protocol of biosimilar drug and guidelines, so far the defendant has not been able to satisfy before the Regulatory Authority as to whether the drug manufactured and marketed by the defendants is biosimilar.

As the final finding in this respect is yet to be arrived, the Court has given the following interim directions:

a) The defendants may continue to manufacture, market and advertise their product under the name CANMAb or Bmab-200 or Hertraz on the basis of the approvals already granted without calling their product as “bio similar” and/ or “bio similar to HERCEPTIN, HERCLON, BICELTIS” or in any way ascribing any bio-similarity with that of the plaintiffs products HERCEPTIN, HERCLON, BICELTIS in any press releases, public announcements, promotional or other in printed form and from relying upon or referring the plaintiffs’ names.

b) The defendants may also manufacture and market the drug by qualifying the INN name Trastuzumab but not to use the said name stand alone on the carton or package insert as a brand name. The defendants No.2 to 4 can use the INN name as Biocon’s Trastuzumab or Mylan’s Trastuzumab wherever applicable to describe the composition of molecule on the product as well as in its insert and not in a prominent manner. The said expression shall be used at the bottom part of the carton and should be in small size letters than their respective brand names.

c) In view of prima facie findings that the use of the data by the defendants in the product insert without undergoing the entire process of the trials is misleading, the defendants are also restrained from using the data relating to manufacturing process, safety, efficacy and tests conducted for the safety of the drugs as complained of by the plaintiffs till the time the final decision on the issue of the bio similarity is made in the present suit.

d) In the event, the defendant No.2 intends to claim bio similar as a description of its product or part of its promotional campaign or otherwise in any other form, the defendant No.2, if so advised, can re-apply the said license before the relevant authorities including defendant no. 1 and in which case, the defendant No.1, the authorities and committees framed therein shall decide the said approval application in accordance with the Rules and Guidelines of 2012 and also the observations made by this court in the present order. In the alternative, the defendant No.2 may await the outcome of the present suit and can continue with the present arrangement as an interim measure.

e) This interim measure is made only in view of the peculiar facts in the present case wherein the defendant No.2 is already in possession of approvals granted rightly or wrongly validity of which is questioned in this suit. All the decisions made by the DCGI and authorities and committees made therein in connection with future approvals shall take into consideration the guidelines of 2012 and also the findings arrived at in the present order by this court.

For those of us who thought that Roche vs CIPLA dispute concerning Erlotinib Hydrochloride was over following from the findings by the Division Bench, here is an update – CIPLA has now filed a SLP before the Supreme Court of India.

In another landmark judgement by the Delhi High Court towards expounding and interpreting the Patent law in India in F-Hoffman La Roche vs CIPLA_2015, the Court not only upheld the validity of the suit patent but also ascertained that the patent is being infringed.

The suit patent (IN196774) was granted in February 2007 by the Controller of Patents, covering patent rights over Erlotinib Hydrochloride molecule which demonstrated breakthrough capabilities as an Epidermal Growth Factor Receptor (EGFR) inhibitor which spiked survival benefit in cancer including non-small cell lung cancer (NSCLC) patients.

This decision is in respect of the appeal/cross-appeal filed against the order of the Single Judge, Justice Manmohan Singh of the Delhi High Court. The Division Bench in the appeal reversed the finding of the Single judge and held that as CIPLA’s Erlocip, admittedly one particular polymorphic form of the Erlotinib Hydrochloride compound (Polymorph B) clearly infringes the IN ‘774 patent. Further, the Bench maintained the finding of the Single judge in terms of validity of the patent. The patent is considered to be non-obvious and complaint with section 8 of the Patents Act.

However, keeping in view of the fact that the life of the patent is soon to expire in March, 2016, the Bench did not grant an injunction as prayed for by Roche against CIPLA, keeping in view that there is no interim injunction enforced against CIPLA. Roche has also been awarded cost of Rs. 5 lakhs.

Hon’ble Justice Mr. A.K. Pathak on October 07, 2015 granted the first ever permanent injunction in a patent infringement suit under the Patents Act 1970. The detailed judgment of 133 pages is in relation to the patent infringement action by Merck against Glenmark with respect to patent number 209816 which covers the type-II diabetes drug sitagliptin.

The judgement restrains the Defendant by a decree of permanent injunction from making, using, selling, distributing, advertising, exporting, offering for sale or deadline in sitagliptin phosphate monohydrate or any other salt of sitagliptin in any form, alone or in combination with one or more other drugs. The Plaintiff has also been entitled to actual costs of the proceedings under the order.

While Merck had claimed infringement of its 209816 patent, Glenmark argued that the product sitagliptin phosphate monohydrate being manufactured by them was actually not covered by the suit patent due to which their activities were not infringing. In addition, Glenmark claimed that Merck’s patent was invalid.

The Hon’ble Court held that since the patent relates to an invention of a chemical molecule/ compound in the medicinal field and is of a highly technical nature, the Court has to go by the opinion of the experts in the field and is not to impose their views over the views of the technical experts, more so when the Judges are not experts in the chemical/medicinal field.

The Hon’ble Court also discredited the independent technical expert of the Defendant as in the opinion of the Court said expert had taken contradictory stands which were in conflict with what was stated in his own publications (e.g. patent documents in which he has been named as an inventor) and in the publications of the Defendant. The Court also observed that the Defendant’s expert witness had a personal interest in sitagliptin since he was named as an inventor in a patent application related to sitagliptin pterostilbene phosphate. Furthermore, the Court observed that the Defendant’s expert witness gave evasive replies to questions which would inconvenience the Defendant. The Court found the Plaintiff’s independent technical expert’s testimony more favourable and reliable and found no reason not to accept the explanation provided by him.

On the question of whether sitagliptin phosphate monohydrate is covered by the suit patent since the suit patent exemplified only the hydrochloride salt of sitagliptin, the Hon’ble Court conceded with the Plaintiff’s independent expert’s testimony that the conversion of a salt to a free base and the free base to another salt was a very basic chemical transformation taught in all sophomore organic chemistry classes. Moreover, the suit patent claims sitagliptin and all its pharmaceutically acceptable salts and the phosphate salt is mentioned as a preferred salt in the specification.

The Court further observed that the Defendant’s technical expert and also the Defendant themselves in their own patent applications relating to sitagliptin have admitted that the salts of sitagliptin are generically encompassed within the scope of the suit patent which also discloses a process for the preparation of the sitagliptin and related compounds. Therefore, sitagliptin phosphate monohydrate is generically disclosed in the suit patent.

On the question of infringement, the Hon’ble Court held that a comparison of the Plaintiffs’ and Defendant’s package insert shows that all the products contain the same compound, i.e, sitagliptin phosphate monohydrate, a DPP-IV inhibitor used for the treatment of type II diabetes. Distinguishing the facts of the present case from those in F Hoffman La Roche v Cipla Ltd. (2012(52) PTC 1(DEL), the Court held that the Plaintiffs in the present case have not sought to establish infringement based on packaging and product inserts alone but also based on ocular and other documentary evidence on record.

The Court also held that the Defendant cannot conveniently disown what has been written on the packagings and the product inserts, which is a disclosure to the public at large including the doctors and consumers of the drug, about the contents used and the utility of the drug.

The Court stated that the use of sitagliptin free base alone in sitagliptin phosphate monohydrate tablet by the Defendant amounts to infringement of the suit patent. All the literature on record indicates that sitagliptin is the DPP-IV inhibitor. It is the sitagliptin free base which is the DPP-IV inhibitor and phosphate salt is used for the delivery of sitagliptin the body. Therapeutic efficacy is not enhanced by sitagliptin phosphate monohydrate since it is sitagliptin itself which is the active moiety and is effective for inhibiting DPP-IV enzyme and is useful for the treatment of type II diabetes. Sitagliptin phosphate monohydrate has enhanced properties in the sense that it has improved physical and chemical properties, but the active moiety is sitagliptin.

On the contention of the Defendant that they were using a process for the manufacture of sitagliptin that was different from the process used by Merck, the Court that no such different process was disclosed in the written statement and counter claim filed by the Defendant and no employee of the Defendant appeared as a witness to prove such a process. The process which was introduced in the evidence of the Defendant’s independent technical expert was not duly proved because he did not have occasion to verify said process having not monitored the manufacturing at any stage or having not involved himself in such a manufacturing process. Further, the independent technical expert did not personally analyse the products of the Defendant so as to verify the process.

The Defendant’s contention that Plaintiffs ought to have proved that Defendant was deploying the same process was considered inadmissible as it was the Defendant who took the plea of using a different process and therefore, should have proved the same, more so when the products of the Plaintiffs and Defendant contain the same chemical compound.

On the issue of obviousness of the suit patent the Hon’ble Court held that the onus to establish obviousness is on the Defendant which they failed to discharge by leading positive evidence. The technical expert of the Defendant has admitted to hindsight which is not permissible in an obviousness analysis. Further, the Plaintiff’s expert pointed to the non-obviousness of the suit patent in his affidavit which opinion remained unshattered in his cross-examination. Mere comparison of chemical structure is not sufficient and picking up parts of a chemical structures of different patents and clubbing them is also not sufficient as this appears to have been done based on hindsight.

On industrial application, the Hon’ble Court held that compounds that are derived from the suit patent will be a product as required under the provisions of the Patents Act and it cannot be denied that sitagliptin free base has therapeutic utility and sitagliptin phosphate monohydrate has better physico-chemical characteristics. Further, sitagliptin phosphate monohydrate is generically covered in the suit patent. There is no requirement under the law that the product has to be under a manufacturing process at the time a patent is granted.

On the issue of insufficient disclosure and broad claiming by way of Markush claims, the Hon’ble Court held that the Markush claims of the suit patent are not different from other patent documents (including those of the Defendant and their expert) which also contain Markush claims.

The suit patent is addressed to a person skilled in the art and not to a lay person. The Defendant themselves acknowledge in their patents that sitagliptin and its pharmaceutically acceptable salts are disclosed in the suit patent. The Defendant cannot be permitted to blow hot and cold in the same breath.

On the ground of non-compliance with section 8 of the Patents Act, the Hon’ble Court was in agreement with the decision of the Divisional Bench in Sukesh Bhel & Anr. Versus Koninklijke Phillips Electronics, that the power of the Court to revoke the patent on the ground of Section 8 violation is discretionary. The Court further ruled that no evidence was led by the Defendant to show that the non-disclosure of information was deliberate or for malafide reasons.

On public interest, the Hon’ble Court held that sale of the drug by the Defendant at a price lower than that of the Plaintiff cannot be a ground to decline injunction against the Defendant. The Court also held that public interest could not be a ground for denying infringement in the instant case as sitagliptin is not the only type II diabetes drugs in the market. There are several other DPP-IV inhibitors available, including, teneligliptin which is also manufactured and marketed by the Defendant.

In view of the foregoing, the validity of the patent was upheld and a permanent injunction was granted.

The Controller of Patents, Mumbai issued an order rejecting a patent application of Pfizer for Tofacitinib for the second time. The primary ground for rejection of Tofacitinib was Section 3(d) and the Controller relied on the Supreme Court’s order on the Glivec case. The Controller said that the claimed form is an enantiomer of a compound (known compound) and the Applicant has failed to establish the enhanced therapeutic efficacy of the claimed compound over the base compound. The Controller held that the base compound is a “known compound” for the purpose of section 3(d) even if the prior art which discloses it was not published before the priority date. The said prior art being Applicant’s own patent application was known to the them.

The Controller also held that the advantage of the claimed form over other possible enantiomer forms of the base compound does not prove enhanced efficacy over base compound.

The Controller also rejected the application on the grounds of Anticipation by prior claiming. The controller held that Example 14 of WO 01/42246 (D1) discloses the compound of present claim without reference to the stereo chemical configuration (base compound) which is also claimed in the prior art. Further the controller held that D1 teaches that the compounds have asymmetric centres and exist in different enantiomeric and diastereomeric forms. D1’s reference to enantiomeric and diastereomeric forms of the compounds was held to represent an unambiguous technical teaching making available to the public all four stereo chemical configurations of the compounds according to example 14. Therefore the form (3R, 4R) of the compound claimed by the applicant was considered disclosed in the prior art. The Controller also considered present form to be anticipated as he held that the Applicant has failed to compare the compound claimed with the compound of prior art D1 to overcome lack of novelty.

This is the second time that the same application has been rejected by the Indian Patent Office. The patent application was rejected for the first time by a different Controller and the Patent office in Mumbai was directed by Intellectual Property Appellate Board (IPAB) to re-consider Pfizer’s patent application on account of flagrant violation of principles of natural justice. The matter was heard afresh by Controller of patents on January 2015. The application has been rejected again by the recent order on the 3rd of September, 2015

The Indian Patent Office issued its order dismissing two pregrant oppositions filed by NATCO and Lupin against Wyeth for their commercial product, Tygacil.

The application claims a composition comprising: (a) tigecycline; (b) a carbohydrate chosen from lactose, mannose, sucrose and glucose; and (c) and an acid or buffer, the molar ratio of tigecycline to the said carbohydrate is between about 1:0.2 to about 1:5 and the pH of the composition is between 3.0 and 7.0.

The Controller opined that the application claims a second generation formulation with selective carbohydrate at a low pH with tigecycline. Experimental results in the specification point to epimerization of tigecycline in presence or absence of lactose and also show that in presence of lactose, the epimerization of tigecycline is less and therefore tigecycline is stabler.

The Controller therefore held that the formulation of the instant invention is not a mere admixture but shows synergism /surprising result and therefore cannot be held under section 3(e) of the Act . The results are not predictive from prior art and hence it is inventive too.

The Controller also held that the composition claim does not attract section 3(d) and in this regard relied on the decision of the IPAB in Allergan Inc. Vs. Ajanta. section 3(d) of the Act considers the following not Patentable: –

“(d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.

Explanation.—For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy;”.

The Controller held that the combination mentioned in the explanation of section 3(d) can only mean a combination of two or more of the derivatives mentioned in the Explanation or combination of one or more of the derivatives with a known substance which may result in a significant difference in efficacy. The claimed composition of the instant invention cannot be stated to be a new form of a known substance and therefore does not attract section 3(d).

The order also discussed legal issues, and in particular discussed if a delay of 28 days to file the reply statement and evidence when considering rule 55(4) of the Patent rules should be condoned. The Controller held that the applicant desired to contest the opposition to safeguard their rights (they timely filed a petition for extension of time and correction of irregularity) and for only a little late in filing the reply statement and evidence, and it would not be proper to debar them to contest on this highly technical issues and that will be against the natural justice.